Optic neuritis is an inflammatory optic neuropathy that occurs in association with Multiple Sclerosis (MS) in about fifty percent of patients. Like other MS lesions, optic neuritis has long been recognized as an inflammatory process involving demyelination of axons. During an acute attack of optic neuritis, vision is altered in the affected eye to varying degrees ranging from subtle visual field, color, or contrast changes with normal visual acuity, all the way to severe visual acuity loss including loss of all light perception. Following an acute attack, patients usually recover most of their visual function. In some patients, however, permanent visual deficits do remain. Recent evidence has suggested that in addition to demyelination, some direct damage to neuronal axons and loss of neurons may occur during acute MS and optic neuritis attacks. The mechanism and extent of such neuronal damage is not known. Using a mouse model of optic neuritis, neuronal damage and cell loss will be examined by the studies in this proposal. The time course of neuronal damage in optic neuritis, and the ability of anti-inflammatory agents to alter this time course, will be used to determine whether neuronal injury occurs as a primary disease process or is secondary to inflammatory processes. Furthermore, the mechanism of neuronal cell loss will be examined. Specifically, gene families involved in the process of apoptotic cell death will be studied in this model. Potential interventions, designed to interfere with the apoptotic process, will be tested. These studies will define important apoptotic pathways involved in optic nerve damage, and will suggest therapeutic designs not only for optic neuritis, but which may be useful in other MS lesions and other processes that damage the optic nerve. The proposed studies are both feasible and take advantage of the principal investigator's experience in apoptosis research and retinal ganglion cell research. At the same time, the proposal provides excellent opportunity for the principal investigator to learn from the mentor's extensive experience with animal models of MS and neuroimmunology. The co-mentor has extensive experience in the clinical diagnosis and management of optic neuritis. This proposal will serve as an ideal platform for the principal investigator to begin a career aimed at understanding mechanisms of optic nerve damage and its correlation to clinical findings. [unreadable] [unreadable]